This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Preeclampsia affects 3-5% of pregnancies and contributes significantly to maternal and neonatal morbidity and mortality. We have generated a novel hypothesis regarding the development of pre-eclampsia that postulates that two primary features contribute independently to its development. One feature is a pre-pregnancy phenotype that includes reduced plasma volume, elevated sympathetic tone, reduced uterine blood flow and enhanced platelet activation. This feature has been suggested by the association of a specific genetic polymorphism of angiotensinogen (TT 235) with an increased risk for pre-eclampsia. This polymorphism has been linked in our preliminary data to key pathophysiologic features of pre-eclampsia, previously thought to be exclusive to pregnancy, in women who are examined prior to pregnancy. The second feature is the physiologic volume expansion of pregnancy. We have theorized that the overt clinical manifestations of pre-eclampsia become apparent in late pregnancy as a result of either 1) a normal volume expansion in women unable to tolerate it due to a chronic adaptation to low intravascular volume (abnormal prepregnancy phenotype) or 2) an excessive volume expansion in women with a normal prepregnancy phenotype (i.e. twins, molar pregnancies). In this grant we propose to examine 3 primary specific aims, employing detailed whole body physiologic measurements in women, that will support this pathophysiologic view of the development of preeclampsia;1) We will confirm that the angiotensinogen genotype that has been linked to preeclampsia in Caucasians and Asians is associated with reduced plasma volume in a nulligravid population and that this plasma volume constriction is associated with elevated sympathetic tone, reduced uterine blood flow and heightened platelet activation prior to pregnancy, 2) As we follow these women into pregnancy we will demonstrate;a) that low prepregnancy plasma volume is associated with elevated sympathetic tone and reduced uterine blood flow in early pregnancy (12 weeks) predisposing to abnormal placentation despite similar plasma volume expansion, and b) that prepregnancy plasma volume is indirectly related to both the change in mean arterial pressure (corrected for plasma volume expansion) and degree of platelet activation in the third trimester, 3) Finally, we will demonstrate that pregnancy results in an increase in both post-puerperal plasma volume and arterial compliance lowering the risk for both preeclampsia in future pregnancies and hypertension in later life. This will be a controlled prospective longitudinal study examining an integrated pathophysiologic mechanism underlying the development of preeclampsia. This study proposes to evaluate a novel hypothesis that synthesizes apparently contradictory data into a single coherent theory.